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Pharmacogenomic Association of Nonsynonymous SNPs in SIGLEC12, A1BG, and the Selectin Region and Cardiovascular Outcomes

McDonough, Caitrin W. ; Gong, Yan ; Padmanabhan, Sandosh ; Burkley, Ben ; Langaee, Taimour Y. ; Melander, Olle LU ; Pepine, Carl J. ; Dominiczak, Anna F. ; Cooper-DeHoff, Rhonda M. and Johnson, Julie A. (2013) In Hypertension 62(1). p.48-54
Abstract
We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a -blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)xtreatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and... (More)
We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a -blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)xtreatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39x10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
antihypertensive agents, -blockers, calcium channel blockers, genetic, variation, hypertension, pharmacogenetics
in
Hypertension
volume
62
issue
1
pages
48 - 54
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000320302600013
  • scopus:84880750541
ISSN
1524-4563
DOI
10.1161/HYPERTENSIONAHA.111.00823
language
English
LU publication?
yes
id
1322eb9d-be3b-4bda-bf1b-d538eb9ebf94 (old id 3979647)
date added to LUP
2016-04-01 11:14:31
date last changed
2020-05-13 01:51:59
@article{1322eb9d-be3b-4bda-bf1b-d538eb9ebf94,
  abstract     = {We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a -blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)xtreatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39x10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.},
  author       = {McDonough, Caitrin W. and Gong, Yan and Padmanabhan, Sandosh and Burkley, Ben and Langaee, Taimour Y. and Melander, Olle and Pepine, Carl J. and Dominiczak, Anna F. and Cooper-DeHoff, Rhonda M. and Johnson, Julie A.},
  issn         = {1524-4563},
  language     = {eng},
  number       = {1},
  pages        = {48--54},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Hypertension},
  title        = {Pharmacogenomic Association of Nonsynonymous SNPs in SIGLEC12, A1BG, and the Selectin Region and Cardiovascular Outcomes},
  url          = {http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00823},
  doi          = {10.1161/HYPERTENSIONAHA.111.00823},
  volume       = {62},
  year         = {2013},
}